Most drugs which humans abuse serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals. Experiments are being conducted to assess neuropharmacological and behavioral mechanisms underlying drug-seeking and drug-taking behavior in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. Currently, studies are focusing on methamphetamine, nicotine and delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana. Numerous attempts to obtain reliable self-administration behavior by laboratory animals with THC have been unsuccessful. In contrast, self-administration behavior has been successfully demonstrated in laboratory animals for almost all other psychoactive drugs abused by humans. From these studies it would seem that marijuana has less potential for abuse than other drugs abused by humans. In previous experiments, we demonstrated for the first time persistent intravenous self-administration behavior by squirrel monkeys for doses of THC comparable to those in marijuana smoke inhaled by humans. THC self-administration behavior was consistently maintained using a fixed-ratio schedule in which every 10th lever-pressing response during a daily one-hr session produced an intravenous (i.v.) injection of 2 to 4 mg/kg of THC followed by a one-min timeout (Tanda et al., Nature Neurosci. 2000, 3, 1073). We have now studied THC self-administration by squirrel monkeys under a more complex, second-order schedule of drug injection. Under this schedule, each completion of a fixed-ratio 10 unit during a 30-min fixed-interval of time produced only a brief visual stimulus (2-sec flash of a light); the first fixed-ratio unit completed after the 30-min interval elapsed produced ten consecutive pairings of the light and i.v. injection of THC and ended the daily session. An advantage of this second-order schedule of drug injection is that drug-seeking behavior during the session occurs in the absence of the direct pharmacological effects of drug (THC) at the end of the session. Responding was consistently maintained when 10 injections of 2 to 8 mg/kg of THC, spaced 2-sec apart, ended each session. Drug-seeking behavior was markedly reduced either by substitution of vehicle for THC or by pre-session treatment with SR141716A, a selective antagonist of CB1 cannabinoid receptors. Drug-seeking behavior under the second-order schedule of i.v. THC injection was comparable in intensity to that maintained by i.v. injection of amphetamine or morphine under similar conditions. In another series of studies, the role of different neurotransmitter systems in the reinforcing effects of methamphetamine is being evaluated in rats trained to i.v. self-administer methamphetamine. We previously reported that rats that actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed marked decreases in somatodendritic dopamine D2 autoreceptor levels in the ventral tegmental area and median and dorsal part of the substantia nigra zona compacta with a corresponding down-regulation of dopamine D1 receptors in the shell of the nucleus accumbens. The purpose of the present study was to determine whether neuroadaptive changes in dopamine receptors in the brains of rats withdrawn for 24 hours from chronic methamphetamine self-administration were persistent changes that could be demonstrated long after withdrawal. In vitro quantitative autoradiography was used to determine densities of dopamine uptake sites and dopamine D1 and D2 receptors in different brain regions following 7- and 30-day periods of withdrawal from chronic methamphetamine self-administration. No changes in dopamine dopamine receptor numbers were detected in any brain region examined in rats self-administering methamphetamine compared with littermates receiving yoked infusions of either methamphetamine or saline. Thus, neuroadaptive changes in densities of dopamine receptors in certain brain areas may contribute to the reinforcing effects of methamphetamine during the acquisition and maintenance phases of self-administration, but do not appear to contribute to the long-lasting neuroadaptive effects of chronic methamphetamine self-administration which may trigger craving and relapse.